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Questions and Answers
What is one of the clinical factors that can influence warfarin dosing?
What is one of the clinical factors that can influence warfarin dosing?
What should be done if the INR is above the therapeutic range?
What should be done if the INR is above the therapeutic range?
Which adverse effect is associated with the use of warfarin during pregnancy?
Which adverse effect is associated with the use of warfarin during pregnancy?
What is a rare complication of warfarin use that occurs several days after treatment initiation?
What is a rare complication of warfarin use that occurs several days after treatment initiation?
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Which of the following is a direct oral anticoagulant?
Which of the following is a direct oral anticoagulant?
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What is the primary mechanism of action of DOACs?
What is the primary mechanism of action of DOACs?
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Which of the following is an antidote for dabigatran?
Which of the following is an antidote for dabigatran?
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Which characteristic is NOT true about all DOACs?
Which characteristic is NOT true about all DOACs?
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What is the role of Factor Xa in the coagulation process?
What is the role of Factor Xa in the coagulation process?
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Which of the following statements about Andexanet alfa is true?
Which of the following statements about Andexanet alfa is true?
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Which drug acts as a reversal agent for factor Xa anticoagulants?
Which drug acts as a reversal agent for factor Xa anticoagulants?
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What is Ciraparantag primarily known for?
What is Ciraparantag primarily known for?
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What type of interactions does Ciraparantag use to bind to anticoagulants?
What type of interactions does Ciraparantag use to bind to anticoagulants?
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Which of the following anticoagulants is NOT predicted to interact with Ciraparantag?
Which of the following anticoagulants is NOT predicted to interact with Ciraparantag?
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What role does some research suggest Ciraparantag may have with factor IXa?
What role does some research suggest Ciraparantag may have with factor IXa?
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What is the primary mechanism of action of warfarin?
What is the primary mechanism of action of warfarin?
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Which factor is NOT typically affected by warfarin treatment?
Which factor is NOT typically affected by warfarin treatment?
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What is a common adverse effect associated with warfarin use?
What is a common adverse effect associated with warfarin use?
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Which of the following is the appropriate treatment for warfarin toxicity?
Which of the following is the appropriate treatment for warfarin toxicity?
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What interaction can significantly influence warfarin efficacy?
What interaction can significantly influence warfarin efficacy?
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How do Direct Oral Anticoagulants (DOACs) primarily work?
How do Direct Oral Anticoagulants (DOACs) primarily work?
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Which of the following is a reversal agent specifically for DOACs?
Which of the following is a reversal agent specifically for DOACs?
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What differentiates newer oral anticoagulants from warfarin?
What differentiates newer oral anticoagulants from warfarin?
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Which CYP enzyme is primarily involved in the metabolism of S-Warfarin?
Which CYP enzyme is primarily involved in the metabolism of S-Warfarin?
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What is the effect of the CYP2C9*2 genotype on enzymatic activity?
What is the effect of the CYP2C9*2 genotype on enzymatic activity?
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What haplotype is associated with decreased warfarin requirements in VKORC1 variants?
What haplotype is associated with decreased warfarin requirements in VKORC1 variants?
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Which CYP2C9 genotype is likely to require the highest dose reduction compared to the wild type?
Which CYP2C9 genotype is likely to require the highest dose reduction compared to the wild type?
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What is the frequency of the CYP2C9*1/*1 genotype in Caucasians?
What is the frequency of the CYP2C9*1/*1 genotype in Caucasians?
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What is the main mechanism of action of Warfarin?
What is the main mechanism of action of Warfarin?
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What is the impact of the VKORC1 non-A/A form on warfarin dosing?
What is the impact of the VKORC1 non-A/A form on warfarin dosing?
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Which CYP2C9 genotype frequency is 1% or lower among Caucasians?
Which CYP2C9 genotype frequency is 1% or lower among Caucasians?
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What is the target INR range for most indications when using Warfarin?
What is the target INR range for most indications when using Warfarin?
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How does Warfarin affect Vitamin K recycling?
How does Warfarin affect Vitamin K recycling?
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Which of the following has the greatest decrease in warfarin dose requirement associated with it?
Which of the following has the greatest decrease in warfarin dose requirement associated with it?
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Which of the following is NOT a CYP isoform involved in Warfarin's metabolism?
Which of the following is NOT a CYP isoform involved in Warfarin's metabolism?
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What condition might result from excessive Vitamin K intake in patients taking Warfarin?
What condition might result from excessive Vitamin K intake in patients taking Warfarin?
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Which enantiomer of Warfarin is more potent?
Which enantiomer of Warfarin is more potent?
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What role does VKORC1 have in relation to Warfarin?
What role does VKORC1 have in relation to Warfarin?
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Why does Warfarin have a slow onset of action?
Why does Warfarin have a slow onset of action?
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Study Notes
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
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Description
This quiz covers the essential aspects of oral anticoagulants, including their mechanisms of action, comparisons with older therapies like warfarin, and factors affecting anticoagulant responses. Dive into details about direct and indirect thrombin inhibitors, adverse effects, and drug interactions to enhance your understanding of anticoagulation therapy.
