Oral Anticoagulants Overview

Oral Anticoagulants

• Oral anticoagulants are primarily used for venous thrombosis
• Parenteral anticoagulants are used in both arterial and venous thrombosis
• Indirect thrombin inhibitors include heparin
• Direct thrombin inhibitors include (obsolete) lepirudin, bivalirudin, and argatroban
• Direct oral anticoagulants (DOACs) are dabigatran, rivaroxaban, apixaban, edoxaban, and betrixaban

Learning Objectives

• Explain the mechanism of action of warfarin
• Identify factors affecting individual warfarin responses
• Discuss warfarin adverse effects
• Detail warfarin toxicity treatment and rationale
• Understand warfarin drug-drug and drug-food interactions
• Explain the mechanisms of action of DOACs
• Discuss reversal agents for DOACs
• Compare and contrast newer oral therapies with warfarin

Coagulation Cascade

• Clotting factors are involved in the cascade
• Prothrombin converts to thrombin
• Thrombin converts fibrinogen to fibrin (soluble to insoluble)
• Platelets form a plug at a damaged blood vessel
• Blood vessel injury triggers the release of clotting factors, leading to vasoconstriction and platelet plug formation, which further leads to the development of the clot.

Activation of Clotting Factors

• Inactive clotting factors contain N-terminal γ-carboxyglutamic acid (Gla)
• Gla binds calcium (Ca2+)
• Synthesis of Gla occurs through γ-glutamly enzyme
• Vitamin K is needed for the synthesis of Gla

Activation of Inactive Clotting Factors and Vitamin K Cycle

• Anti-coagulant proteins C and S affect inactive clotting factors II, VII, IX, and X
• Vitamin K is reduced, and then oxidized, with y-glutamly, to recycle into the vitamin K active form
• Vitamin K dependent coagulation factors and anticoagulants are influenced by the half-life of the proteins

Oral Anticoagulants: Warfarin

• Warfarin is a synthetic congener of dicoumarol
• Originally used as a rodenticide
• Warfarin works by inhibiting vitamin K epoxide reductase (VKORC1), a process in hepatocytes. This enzyme is needed for the recycling of vitamin K, which is critical to activating clotting factors II, VII, IX, and X.

Warfarin: Mechanism of Action

• Warfarin is a vitamin K antagonist
• Warfarin inhibits the recycling of vitamin K
• Warfarin prevents the carboxylation of newly synthesized clotting factors
• Warfarin-mediated blockage of the vitamin K cycle inhibits the activation of clotting factors

Warfarin: Clinical Use

• Warfarin prevents and treats venous thrombosis
• Warfarin's onset of action is slow
• INR (international normalized ratio) is used to monitor warfarin therapy
• Target INR is typically 2-3 for most indications

Drug and Other Interactions

• Warfarin absorption can be reduced by cholestyramine
• Warfarin is a racemic mixture of R and S enantiomers (S more potent)
• S-warfarin is metabolized by CYP2C9
• R-warfarin is metabolized mainly by CYP1A2 and CYP3A4
• Some drugs can stereoselectively inhibit warfarin metabolism
• Excessive vitamin K intake can cause warfarin resistance
• Patients must report medication changes

Major CYP Isoforms Involved in Warfarin Metabolism

• CYP2C9 plays a vital role in warfarin activation, specifically the S-form
• Warfarin is metabolized by CYP1A1, CYP1A2, CYP3A4, and CYP2C9
• Warfarin metabolism is prone to genetic polymorphisms
• VKORC1 is prone to genetic polymorphisms, too

Examples of Drug Interactions

• Various drugs (Amiodarone, Cimetidine, Disulfiram, Metronidazole, Fluconazole, Phenylbutazone, Sulfinpyrazone, and Trimethoprim-sulfamethoxazole) can interfere with warfarin metabolism, potentially leading to either increased or decreased prothrombin time.
• Other factors that may influence warfarin's effect include liver disease, hyperthyroidism, hypothyroidism, and hereditary resistance.

Warfarin Pharmacogenetics: Polymorphisms in Metabolizing Enzymes (CYP2C9)

• More than 30 CYP2C9 variants exist.
• CYP2C9 variants affect warfarin pharmacokinetic
• CYP2C92 and CYP2C93 mutations, specifically missense mutations, can lead to reduced enzymatic activity and necessitate a dose adjustment to maintain desired anti-coagulation effects.

Warfarin Pharmacogenetics: Genetic Polymorphisms in VKORC1

• VKORC1 gene promoter region has polymorphisms such as -1639G>A
• Other intronic polymorphisms include 497T > G or 5808, 1173C > T or 6484, 1542G>C or 6853, and 2255C > T or 7566
• VKORC1 variants influence warfarin pharmacodynamics
• Individuals with certain VKORC1 genetic variants may require lower warfarin doses compared to others.

Effect of CYP2C9 Genotypes and VKORC1 Haplotypes on Warfarin Dosing

• Data from studies involving Caucasian, African American, and Asian populations show varying frequencies for different genotypes/haplotypes, indicating the impact of race on the frequency of the genotypes/haplotypes
• Different CYP2C9 and VKORC1 genotypes have impact on the dose reduction compared with the wild type

Genetic Determinants of Response to Warfarin During Initial Anticoagulation

• Genetic variations in VKORC1 and CYP2C9 affect the time it takes for individuals to achieve a therapeutic INR (International Normalized Ratio) during warfarin treatment
• Genetic variation may contribute to differences in the time needed to attain the therapeutic INR level

Dosing Considerations

• Clinical factors (age, race, body weight, sex) and concurrent medications, diet, and comorbidities influence warfarin dosing
• Genetic variations (CYP2C9 and VKORC1 genotypes) influence dosing
• The onset of action of warfarin is delayed due to the half-life of vitamin K-dependent clotting factors and anticoagulant proteins

Warfarin: Toxicity

• Bleeding is a common complication of warfarin toxicity
• INR exceeding therapeutic levels may necessitate discontinuation or dosage adjustment of warfarin
• A vitamin K treatment is recommended for cases of INR exceeding 10 without bleeding
• Four-factor concentrate can help treat warfarin-associated serious bleeding (contains factors II, VII, IX, and X), requiring additional vitamin K for optimal effects
• Warfarin is contraindicated in pregnancy due to possible birth defects
• Skin necrosis can rarely occur, potentially due to an imbalance between anticoagulant protein C and coagulation factors

Direct Oral Anticoagulants (DOACs)

• DOACs provide a quick onset of action, owing to existing clotting factors
• DOACs typically do not require routine monitoring like warfarin.
• DOACs generally have fewer drug interactions compared to warfarin.
• All DOACs are p-glycoprotein substrates

Example: Dabigatran

• Dabigatran is a thrombin inhibitor
• Dabigatran is a pro-drug, which changes to it active form in the liver
• Idarucizumab is a reversal agent for dabigatran

Example: Rivaroxaban and Apixaban

• Rivaroxaban and apixaban are Factor Xa inhibitors, blocking factor Xa binding to prevent prothrombin from converting to thrombin.
• Andexanet alfa is the reversal agent for the anticoagulant effects of rivaroxaban and apixaban.

Example: Factor Xa Inhibitor

• Factor Xa is crucial in both the intrinsic and extrinsic coagulation pathways
• S419 is involved in Factor Xa converting prothrombin to thrombin within the prothrombinase complex
• Factor Xa inhibitors like rivaroxaban and apixaban affect the catalytic site and prevent thrombin formation

Example: Factor Xa inhibitor antidote Andexanet Alpha

• Andexanet Alpha is a recombinant protein derived from human coagulation factor Xa
• S419A and lack of GLA domain feature make it specific for factor Xa inhibitors
• Sequesters with high specificity for factor Xa inhibitors

Ciraparantag

• Ciraparantag is an investigational reversal agent also known as PER977 and aripazine
• Ciraparantag is a cationic molecule
• It interacts through non-covalent hydrogen bonds and charge-charge with anticoagulant targets
• Some studies are questioning its ability to directly interact with specific anticoagulants and suggest a role in factor IXa activation