Podcast
Questions and Answers
What is the primary mechanism by which aspirin inhibits platelet aggregation?
What is the primary mechanism by which aspirin inhibits platelet aggregation?
In which condition is low-dose aspirin primarily recommended for use?
In which condition is low-dose aspirin primarily recommended for use?
Which antiplatelet agent is commonly used when aspirin is contraindicated?
Which antiplatelet agent is commonly used when aspirin is contraindicated?
What is a common side effect associated with aspirin usage?
What is a common side effect associated with aspirin usage?
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Which of the following correctly describes the action of Clopidogrel?
Which of the following correctly describes the action of Clopidogrel?
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What is the role of Antithrombin in the clotting mechanism?
What is the role of Antithrombin in the clotting mechanism?
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What should be weighed against the benefits of using aspirin in patients without previous cardiovascular disease?
What should be weighed against the benefits of using aspirin in patients without previous cardiovascular disease?
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Which of the following is NOT a type of antiplatelet drug?
Which of the following is NOT a type of antiplatelet drug?
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For which group of patients should antiplatelet agents be used with caution?
For which group of patients should antiplatelet agents be used with caution?
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Which of the following antiplatelet agents are considered glycoprotein IIb/IIIa antagonists?
Which of the following antiplatelet agents are considered glycoprotein IIb/IIIa antagonists?
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What is the primary therapeutic use of fibrinolytic agents such as Streptokinase?
What is the primary therapeutic use of fibrinolytic agents such as Streptokinase?
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What factors does Protein C inactivate to help regulate clotting?
What factors does Protein C inactivate to help regulate clotting?
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Which statement about antiplatelet agents is true?
Which statement about antiplatelet agents is true?
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Which mechanism is utilized by the Tissue Factor Pathway Inhibitor?
Which mechanism is utilized by the Tissue Factor Pathway Inhibitor?
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What happens to Plasminogen in the clotting process?
What happens to Plasminogen in the clotting process?
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Which of the following drugs is categorized as a glycoprotein IIb/IIIa inhibitor?
Which of the following drugs is categorized as a glycoprotein IIb/IIIa inhibitor?
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Which anticoagulants are used in combination with heparin and low-dose aspirin for the prevention of ischaemic cardiac complications?
Which anticoagulants are used in combination with heparin and low-dose aspirin for the prevention of ischaemic cardiac complications?
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What is the primary role of Antithrombin III in the mechanism of UFH?
What is the primary role of Antithrombin III in the mechanism of UFH?
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Which of the following is NOT classified as a vitamin K antagonist?
Which of the following is NOT classified as a vitamin K antagonist?
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Which drug is NOT classified as an indirect parenteral anticoagulant?
Which drug is NOT classified as an indirect parenteral anticoagulant?
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What is the expected time for maximal anticoagulation effect after IV administration of UFH?
What is the expected time for maximal anticoagulation effect after IV administration of UFH?
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How does UFH primarily exert its anticoagulant effect?
How does UFH primarily exert its anticoagulant effect?
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What is the role of aPTT in the management of patients receiving UFH?
What is the role of aPTT in the management of patients receiving UFH?
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Which of the following combinations is used for treating unstable angina or NSTEMI?
Which of the following combinations is used for treating unstable angina or NSTEMI?
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What is the primary use of Prasugrel?
What is the primary use of Prasugrel?
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Which of the following statements about Prasugrel is true?
Which of the following statements about Prasugrel is true?
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What is a significant side effect of Dipyridamole?
What is a significant side effect of Dipyridamole?
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Which risk factor is associated with increased intracranial hemorrhage when using Ticagrelor?
Which risk factor is associated with increased intracranial hemorrhage when using Ticagrelor?
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What distinguishes Ticagrelor from Clopidogrel?
What distinguishes Ticagrelor from Clopidogrel?
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For which combination is Dipyridamole typically used?
For which combination is Dipyridamole typically used?
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What do the Glycoprotein IIb/IIIa receptor inhibitors primarily prevent?
What do the Glycoprotein IIb/IIIa receptor inhibitors primarily prevent?
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Which of the following is a common side effect of Ticagrelor?
Which of the following is a common side effect of Ticagrelor?
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Study Notes
Clotting Mechanism 2 - Antithrombotic Agents
- Learning Objectives
- Understand and describe different classes of drugs that affect blood coagulation, and their mechanism of action
- Understand various indications and therapeutic uses of anticoagulants and antiplatelet agents
- Understand pros and cons of using various antithrombotic agents, adverse drug reactions, contraindications, and monitoring
Inhibitors of Clotting Mechanism
-
Inhibitors
- Antithrombin: Inhibits factors IIa, IXa, and Xa
- Protein S: Co-factor for activation of protein C
- Protein C: Inactivates factors Va and VIIIa
- Tissue factor pathway inhibitor: Inhibits activity of factor VIIa
- Plasminogen: Converted to plasmin via t-PA, causing lysis of fibrin to fibrin degradation products
Selection of Agents
- Anticoagulants (heparin (UFH), LMWH, Warfarin) are used in treatment and prevention of arterial and venous thrombi
- Platelet aggregation inhibitors (aspirin, clopidogrel) are used in prevention of arterial thrombi alone or with anticoagulants
- Fibrinolytic agents (Streptokinase) are used in rapid dissolution of thromboembolism, particularly during myocardial infarction (MI)
Overview of Drugs Affecting Blood Coagulation
- Diagram illustrates the various drugs (aniticoagulants, antiplatelet, fibrinolytic) and their relation to different clotting factors.
Antiplatelet Agents
- Antiplatelet drugs inhibit platelet aggregation
- Used in management of arterial thrombosis
- Not used in management of venous thromboembolism (VTE)
- Main types include Thienopyridines (Clopidogrel, Prasugrel, Ticlopidine), Glycoprotein IIb/IIIa inhibitors (Abciximab, Eptifibatide, Tirofiban), and others (Aspirin, Dipyridamole, Ticagrelor)
- Thromboxane TXA2 promotes platelet aggregation, while prostacyclin PGI2 inhibits it; cyclooxygenase enzyme produces both and balance is crucial
- Asprin irreversibly inhibits cyclo-oxygenase, altering balance between TXA2 and PGI2. Used in arterial thrombosis (AMI, angina, CABG, transient ischemic attack, etc)
- Clopidogrel and Ticlopidine inhibit ADP-dependent platelet aggregation; additive effects with aspirin.
- Inhibitors of glycoprotein (GP IIb/IIIa) receptors (e.g., Abciximab, Tirofiban, Eptifibatide) inhibit various agonists (ADP, TXA2) because various activation pathways converge on these receptors.
Aspirin
- Mode of Action: Irreversibly inhibits cyclooxygenase, reducing thromboxane A2 synthesis for the platelet's lifespan
- Low-dose (75-325mg daily) recommended for preventing serious vascular events in high-risk patients (post MI, angina, PVD, previous stroke, etc.)
- Benefits in prevention of cardiovascular (CV) events need to be weighed against risks of GI and intracranial bleeding
- Common side effects: GI irritation, increased bleeding time, allergy (bronchospasm, urticaria, rhinitis)
- Rarer side effects: GI and intracranial bleed
- Category C in pregnancy; low doses are considered safe, but typically avoided in the third trimester
Clopidogrel and Prasugrel
- Clopidogrel and Prasugrel block the platelet ADP receptor (P2Y12), preventing activation of the platelet glycoprotein IIb/IIIa complex and thrombus formation; drug affects lifespan of platelets
- Prolong bleeding time, so use cautiously in patients with bleeding disorders
- Used in patients with aspirin contraindications or in combination with aspirin for patients with a cardiovascular event or after stenting
Prasugrel
- Newer agent
- Used to prevent atherothrombotic events (with aspirin) in ACS, including STEMI and NSTEACS managed with PCI
- Superior to Clopidogrel in primary outcomes (death, stroke, MI) and secondary outcomes (stent thrombosis) but a higher risk of major (including fatal) bleeding was noted
- Does not differ from Clopidogrel in terms of overall mortality
- Starting loading dose of 60mg, then reduced to 10mg daily (5mg if older than 75) with 75-150mg aspirin
Dipyridamole
- Inhibits platelet function by inhibiting phosphodiesterase, thereby increasing platelet cAMP which blocks platelet response to ADP
- Used in combination with warfarin for patients with prosthetic heart valves
- Used in combination with aspirin for secondary prevention of stroke, benefit over aspirin alone unknown
- Side effects include vasodilation (headache, hot flushes, hypotension, tachycardia) and allergic reactions (rash, urticaria, bronchospasm)
Ticagrelor
- Newer drug that binds reversibly to the P2Y12 receptor, inhibiting platelet aggregation
- Indicated for use in ACS (with aspirin)
- 12-month study shows higher efficacy than Clopidogrel with aspirin for preventing CV events in ACS
- Significant reductions in MI and vascular death but a non-significant increase in stroke was noted
- Incidence of total bleeding similar, but risk of intracranial hemorrhage was higher with Ticagrelor
- Risk-benefit of Ticagrelor with aspirin doses >150mg daily not favourable
- Side effects include bleeding, nausea, diarrhea, headache, and non-cardiac chest pain
Glycoprotein IIb/IIIa Receptor Inhibitors
- Abciximab, Eptifibatide, Tirofiban prevent fibrinogen binding to platelets, thereby reducing platelet aggregation
- Used with heparin and low-dose aspirin for preventing ischemic cardiac complications following percutaneous transluminal coronary interventions (PTCA, stenting)
- Abciximab and Eptifibatide are used for treatment of unstable angina or NSTEMI
- Eptifibatide and Tirofiban are given intravenously (IV)
Anticoagulants
- Divided into Indirect Parenteral Anticoagulants (heparin), Direct thrombin inhibitors (Dabigatran, Bivalirudin), Vitamin K antagonists (Warfarin, Phenindione), and Factor Xa inhibitors (Apixaban, Fondaparinux, Rivaroxaban).
- Warfarin was originally only oral anticoagulant
- Newer agents have reduced and improved classification
Indirect Parenteral Anticoagulants (IPAs) - Heparin
- Mixture of sulfated glycosaminoglycans extracted from porcine or bovine lung (5000-30,000 molecular weight)
- Rapidly-acting parenteral anticoagulant used for acute treatment or prophylaxis of thromboembolic disorders
- UFH affects thrombin indirectly by binding to antithrombin III, leading to rapid anticoagulation after IV injection
- Antithrombin III inhibits thrombin (factor Ila) and factor Xa, along with IX, XI and XII
- Binding of heparin to antithrombin III changes conformation, enabling rapid inhibition of thrombin (except thrombin bound to fibrin) and factor Xa; requires monitoring of activated partial thromboplastin time (aPTT)
IPAs – LMWHs and Danaparoid
- Dalteparin, Enoxaparin, Nadroparin are low molecular weight heparins (LMWHs)
- Danaparoid is a low molecular weight heparinoid
- Fragments produce by chemical/enzymatic breakdown of heparin
- Like heparin, they enhance the effect of antithrombin III, but have a higher ratio for factor Xa Inhibition than factor Ila Inhibition (selective factor Xa activity).
- LMWHs still have some risk of bleeding despite aimed antithrombotic activity
- Danaparoid is a more selective inhibitor of factor Xa compared to LMWHs
- Monitoring using anti-factor Xa is only considered for patients with high bleeding risk. (No evidence that monitoring reduces bleeding risk, APTT not monitored)
- Bleeding less, immune-mediated thrombocytopenia lower, and renal impairment higher (reduce dose) than UFH
Direct Thrombin Inhibitors (DTIs)
- Bind directly to thrombin to block its effect.
- Dabigatran (oral) and bivalirudin (parenteral) are commonly used.
- Thrombin central in clotting by converting fibrinogen to fibrin and activating factors V, VIII and XI and platelets.
- DTIs have both antiplatelet and anticoagulant effects.
Direct Thrombin Inhibitors (DTIs) – Dabigatran
- Prevention of VTE in hip/knee replacement, and treatment of acute VTE.
- Also for use in non-valvular AF and a high risk of systemic embolism
- Drug interactions (Clarithromycin, Ketoconazole, Verapamil) can increase or decrease efficacy
- Common side effects include gastritis, dyspepsia, and GI bleeding.
- Counseling on not missing doses, not opening/chewing, taking at the same time of day, monitoring for bleeding symptoms (like warfarin).
- Reversal agent = Idarucizumab
Factor Xa Inhibitors
- Fondaparinux (SC), Apixaban (oral), Rivaroxaban (oral) selectively inhibit factor Xa by blocking the production of thrombin, conversion of fibrinogen to fibrin, and thrombus development.
- Used for prevention of venous thromboembolism, especially in high-risk orthopaedic surgery (hip fracture or replacement, knee):
- Apixaban and Rivaroxaban have similar onset and half-life (approx 12 hours). Apixaban taken twice daily, while Rivaroxaban taken once daily
- Bleeding is possible side effect
- Concomitant use with aspirin or other drugs increases risk of bleeding
Oral Anticoagulants (Warfarin)
- Oral anticoagulant with delayed onset of effect that acts as a vitamin K antagonist
- Vitamin K essential for conversion of clotting factors II, VII, IX and X and protein C & S
- Concentration of these clotting factors diminishes gradually causing delayed onset of anticoagulant action (approx 5-7 days)
- Warfarin is fully absorbed via the GI tract (bioavailability ≈100%)
- Prothrombin time (PT/INR) is the mandatory monitoring parameter for warfarin therapy
Warfarin —Mechanism of Action
- Warfarin inhibits Vitamin K-dependent carboxylase, a liver enzyme that is necessary for the synthesis of functional clotting factors (II, VII, IX, X) and proteins C and S; this means they will be less active.
- When warfarin is taken, and the clotting factors decrease, this will cause delayed response
- Diagram depicts how warfarin impacts the hepatic synthesis of vitamin K-dependent clotting precursors
Pharmacologic activity of Warfarin
- Warfarin (an oral anticoagulant) takes time to exert full anticoagulant effect
- So, concurrent heparin therapy is often initiated until warfarin reaches full effect: This is known as bridging therapy
- Clotting factors have varying half lives which accounts for the time lag
- Warfarin also affects these clotting factors
Uses of Warfarin
- Gold standard for long-term oral anticoagulation in the prevention (prophylaxis) and treatment of DVT, atrial fibrillation with embolization, pulmonary embolism (PE), myocardial infarction (MI), and thrombus formation after valve replacement.
Use of Warfarin — Initiation of Therapy
- Heparin given concurrently until INR shows adequate warfarin response (5-6 days including at least 2 days in therapeutic range)
- Regular monitoring needed for therapy adjustment as indicated by drug interactions and coexisting diseases
- Large alterations in intake of Vitamin K necessitate monitoring INR values (2-3 times per week, then weekly for 4 weeks - 4-6 weeks once stable)
Use of Warfarin — Dosage
- Dosage is individualized, based on Prothrombin time (PT), which is reported as INR
- International Normalised Ratio (INR) adopted by the WHO in 1983
- Standardizes PT reporting across labs, hospitals and countries
- Balance between thrombosis & haemorrhage considered in therapeutic range
- Usual recommendations for INR ranges differ depending on patient scenarios (AF, DVT, PE, bioprosthetic heart valve, mechanical prosthetic valve)
Use of Warfarin — Contraindications
- Bleeding disorders, previous GI bleed, hemorrhagic retinopathy, intracerebral aneurysm/hemorrhage
- Severe hypertension, bacterial endocarditis
- Alcoholism, unsupervised dementia and frequent falls
- Renal and hepatic impairment.
- Caution with elective surgery (stop warfarin several days before or reduce dose if necessary, e.g., people with artificial heart valves).
- Avoid in pregnancy (teratogenicity and fetal/placental hemorrhage)
Use of Warfarin — Drug Interactions
- Many drugs interact with warfarin, resulting in increased or decreased anticoagulant effect.
- Mechanisms include decreased hepatic synthesis of procoagulant factors, inhibition of enzymatic metabolism of warfarin, accelerated metabolism of warfarin due to hepatic microsomal enzyme activity, alteration of procoagulant synthesis or catabolism, increased receptor affinity for warfarin, decreased vitamin K synthesis due to alterations in intestinal flora, displacement of warfarin from protein-binding sites, and interference with enterohepatic circulation of warfarin.
- Options to consider when an interactant drug is identified and it is difficult to determine the balance - Substituting with drug that doesn't interact, or adjusting dose of warfarin. Ongoing monitoring is crucial if a competing drug is stopped.
NOACs vs DOACs
- NOACs/DOACs = Novel/Direct-Acting Oral Anticoagulants
- Used in situations like heparin and warfarin
- Not used in valvular AF
- Interactions: strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, HIV protease inhibitors and inducers like rifampicin, St. John's wort, carbamazepine)
- Rivaroxaban once daily, like warfarin
NOACs vs Warfarin
- Consider NOAC over warfarin if time in therapeutic range (TTR) is less than 65% over six months in AF
- Patient taking lots of interacting drugs e.g., frequent antibiotic courses
- High alcohol intake (binge drinking)
- Unable to cope with varying warfarin doses.
NOACs - Potential Limitations
- Lack of validated tests to monitor anticoagulant effect
- No established therapeutic range
- No antidote
- Difficulty in assessment of compliance
- Unknown potential for long-term adverse effects, cost-effectiveness
- Lack of head-to-head studies comparing new anticoagulants
- New agents tested for some, but not all indications
- Lack of evidence surrounding risks & benefits of combination antithrombotic therapy
Further Information/Additional Readings
- Textbook chapter on thrombosis (p376-388)
- British National Formulary 84 (Sept 2022-March 2023) Chapter 2.3 Blood Clots p124-154
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Description
This quiz covers the mechanisms and therapeutic uses of various antithrombotic agents, including anticoagulants and antiplatelet drugs. You will learn about their modes of action, indications, advantages, and adverse effects. Test your understanding of how these medications influence blood coagulation.
