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Questions and Answers
What initiates the blood coagulation cascade?
Which of the following anticoagulants is a direct thrombin inhibitor?
What is the primary monitoring test for the anticoagulation effect of unfractionated heparin (UFH)?
What is a characteristic of low molecular weight heparins (LMWHs) compared to unfractionated heparin (UFH)?
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What is the primary antidote for unfractionated heparin (UFH)?
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Which of the following statements about heparin is FALSE?
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Which of the following agents is associated with a risk of heparin-induced thrombocytopenia (HIT)?
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Which of the following conditions is NOT commonly treated with anticoagulants?
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Which direct thrombin inhibitor is available in an oral form?
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Which component is primarily affected by fondaparinux?
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What is a key advantage of oral direct thrombin inhibitors compared to other anticoagulants?
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How does Protein C contribute to the regulation of the clotting cascade?
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Which of the following is NOT a characteristic of direct oral factor Xa inhibitors?
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What is the role of idarucizumab in the context of dabigatran?
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Which of the following drug interactions could potentially increase the level of dabigatran?
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Which characteristic is typically associated with prolonged use of unfractionated heparin?
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What does Rivaroxaban primarily treat?
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Which factor does Warfarin inhibit to exert its anticoagulant effect?
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What is the main reversing agent for Direct Oral Factor Xa inhibitors?
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Which of the following is not a toxic effect associated with Factor Xa inhibitors?
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What clinical condition is Apixaban primarily used to prevent?
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Which characteristic does not typically apply to Warfarin?
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What must occur for Warfarin to achieve its anticoagulant effect?
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What is the primary mechanism of action of Direct Oral Factor Xa inhibitors?
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What is the primary method to monitor the effectiveness of warfarin therapy?
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Which drug class is known to induce cytochrome P450 and decrease the anticoagulant effect of warfarin?
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What is a critical contraindication for the use of warfarin?
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Which of the following is an adverse effect of warfarin that involves painful lesions on the toes?
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What is the action taken for rapid reversal of warfarin?
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When does the prothrombin time return to normal after stopping warfarin?
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What age group is at increased risk of bleeding when using warfarin?
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Which of the following is NOT a Direct Oral Anticoagulant (DOAC)?
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What is the primary function of blood clots in the body?
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Which disorder is characterized by unpredictable bleeding into deep tissues?
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What type of thrombus is primarily found in arteries and is rich in platelets?
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What condition is caused by a thrombus breaking off and traveling to the lungs?
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In which condition do problems in atrial contraction increase the risk of blood stasis?
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Which of the following statements regarding thrombus formation is true?
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What is the primary characteristic of venous clots?
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What condition is described as unwanted clotting within a blood vessel?
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Study Notes
Blood Clots
- Important physiological process, prevent excessive bleeding
- Body naturally dissolves the clot once the injury is healed
- Clots inside vessels without injury or clots that do not dissolve naturally are dangerous
- Clots can occur in veins or arteries
Disorders in Coagulation
- Hemostasis maintains blood fluidity, repairs vascular injury, limits blood loss, preventing tissue occlusion
- Platelet defects e.g. von Willebrand disease causes bleeding from surfaces (gingiva, skin, heavy menses).
- Defects in the clotting mechanism e.g. haemophilia leads to bleeding into deep tissues such as joints, muscle, retroperitonium.
- Platelet-rich thrombi (white thrombi) occur at high flow rate in arteries
- Venous clots (red thrombi) are rich in fibrin and trapped red blood cells
Blood Clots in the Body
- Thrombus is an unwanted clot in a blood vessel, blood flow is sluggish, accumulation of activated clotting factors.
- Deep vein thrombosis (DVT) is a clot in a major vein of the leg/arms, pelvis or other large veins
- A part of a thrombus can break off and travel to the heart or lungs, lodging there causing impaired blood flow
- Pulmonary embolism (PE) is a blood clot in the lungs
- Atrial fibrillation (AF) causes problems with the atrial contraction, leading to an increased risk of blood stasis, promoting thrombus formation.
- A thrombus in the heart can travel to the brain and cause cerebral embolism (stroke).
The Clotting Cascade
- Coagulation is the transformation of soluble fibrinogen to insoluble fibrin
- Tissue factor (TF) initiates the cascade by binding to factor VIIa
- Antithrombin (AT) is an endogenous anticoagulant
- Protein C and Protein S attenuate the blood clotting cascade
Anticlotting Drugs - Uses
- Used for the treatment and prevention of myocardial infarction, ischemic stroke in patients with AF, and DVT
- Anticoagulant and thrombolytic drugs are effective in the treatment of venous and arterial thrombosis
- Antiplatelet drugs treat only arterial disease.
Anticoagulants
- Inhibit the formation of fibrin clots.
- Heparin and related products, direct thrombin and factor X inhibitors, and coumarin derivatives
Heparin
- Large sulfated polysaccharide polymer
- Naturally occurring
- Molecules vary in size between 5,000 and 20,000
- Highly acidic
- Administered intravenously or subcutaneously
- Risk of hematoma with intramuscular administration.
Heparin - Mechanism and Effects
- Unfractionated heparin (UFH) is an indirect thrombin inhibitor. It binds to antithrombin III (ATIII).
- The heparin–ATIII complex irreversibly inactivates thrombin and other factors, particularly factor Xa.
- Heparin acts on preformed blood components, causing immediate anticoagulation.
- Anticoagulation effects are monitored by the activated partial thromboplastin time (aPTT) test.
Low Molecular Weight Fractions
- Dalteparin, enoxaparin, nadroparin: molecular weight 2000–6000
- Better bioavailability and longer duration of action than UFH
- Administered subcutaneously once or twice a day
- Fondaparinux: active pentasaccharide, chemically related to LMW heparin
- Selective inhibitor of factor Xa with no effect on thrombin
- Administered subcutaneously once daily
LMW Heparins
- Enoxaparin, dalteparin, and tinzaparin and fondaparinux bind ATIII.
- Also inhibit factor Xa
- LMW heparin–ATIII and fondaparinux–ATIII complexes have a more selective action
- They have no effect on thrombin.
Heparin - Clinical Use
- Rapid effect
- Common uses: DVT, pulmonary embolism, acute myocardial infarction.
- Combined with thrombolytics for revascularization
- Combined with glycoprotein IIb/IIIa inhibitors during angioplasty and placement of coronary stents.
- Does not cross the placental barrier – safe in pregnancy.
- LMW heparins & fondaparinux - similar clinical applications to heparin
Heparin - Toxicity & Reversal
- Bleeding
- May result in hemorrhagic stroke
- Antidote for UFH is Protamine sulphate
- Protamine partially reverses effects of LMW heparins, no effect on fondaparinux
- UFH causes moderate transient thrombocytopenia
- Heparin-induced thrombocytopenia (HIT) - severe thrombocytopenia and thrombosis in those who produce an antibody that binds to a complex of heparin and platelet factor 4
- LMW heparins and fondaparinux are less likely to cause HIT
- Prolonged use of UFH is associated with osteoporosis.
Direct Thrombin Inhibitors
- Based on proteins made by Hirudo medicinalis
- Desirudin and bivalirudin are modified forms of hirudin
- Argatroban is a small molecule with a short half-life.
- Dabigatran is the only orally active direct thrombin inhibitor.
Direct Thrombin Inhibitors – Clinical Uses
- MOA: Binds to the active site of thrombin and to thrombin substrates.
- The action of these drugs is monitored with the aPTT lab test
- Dabigatran:
- Prevention of stroke and systemic embolism in non-valvular AF
- Prophylaxis of venous thromboembolism (VTE) following hip or knee replacement surgery and
- Reduction of the risk of recurrent VTE
Advantages of oral direct thrombin inhibitors
- Predictable pharmacokinetics - fixed dosing
- Predictable immediate anticoagulant response that makes routine monitoring or overlap with other anticoagulants unnecessary.
Toxicity & Reversal
- Bleeding
- CI: Concomitant administration with heparins/warfarins/thrombolytic agents, GP IIb/IIIa inhibitors, clopidogrel, ticlopidine
Drug Interactions
- Itraconazole, tacrolimus, ketoconazole - increase the level of dabigatran by P-glycoprotein (MDR1) efflux transporter
- Idarucizumab is a humanized monoclonal antibody Fab fragment that binds to dabigatran and reverses the anticoagulant effect.
Direct Oral Factor Xa inhibitors
- Rivaroxaban, apixaban (available in SA), and edoxaban
- Rapid onset of action and shorter half-lives than warfarin.
- Fixed oral doses and do not require monitoring.
- Undergo cytochrome P450-dependent and cytochrome P450-independent elimination.
MOA:
- Bind directly to and inhibit both free factor Xa and factor Xa bound in the clotting complex.
Direct Oral Factor Xa inhibitors- Clinical Use
- Rivaroxaban:
- Prevention and treatment of VTE following hip or knee surgery
- Prevention of stroke in patients with AF, without valvular heart disease.
- Apixaban - Prevention of embolic stroke in patients with non-valvular AF
Toxicity & Reversal
- Can cause bleeding.
- Reversal agent is andexanet alfa.
Warfarin and Other Coumarin Anticoagulants
- Small, lipid-soluble molecules
- Oral administration
- Readily absorbed
- Highly bound to plasma proteins (>99%)
- Metabolised by cytochrome P450 enzymes
Warfarin inhibits Vitamin K epoxide reductase (VKOR)
- VCOR converts vitamin K epoxide to reduced Vitamin K
- Vitamin K dependent factors - thrombin and factors II, VII, IX, and X
- Clotting factors have half-lives of 8–60h.
- Anticoagulant effect only after the elimination of the normal preformed factors (4-5 days).
- Mostbauer, Halyna & Nishkumay, Olga & Rokyta, Oksana & Vavryniuk, Valeriia.(2022).Warfarin resistance: possibilities to solve this problem.A case report.The Journal of international medical research. 50. 3000605221103959. 10.1177/03000605221103959.
Warfarin – long half-life (40hrs)
- Takes up to 5 days for the prothrombin to return to normal after stopping warfarin.
- Reversed with phytomendione (vitamin K), but requires the synthesis of new clotting factors, slow action (6–24 h)
- Rapid reversal – transfuse with fresh or frozen plasma that contains normal clotting factors.
- Monitored by the prothrombin time (PT) test.
Warfarin – Clinical Use
- Prevention and control of thromboembolism
- ↓ thromboembolism in patients with AF & prosthetic heart valves
Toxicity
- Bleeding
- Contraindicated: pregnancy, recent stroke, intracerebral bleeding, aneurysms.
- Narrow therapeutic window
- Monitor INR (International normalized Ratio).
Warfarin – Drug Interactions
- Metabolized in the liver to inactive 7-hydroxywarfarin.
- Cytochrome P450-inducing drugs (carbamazepine, phenytoin, rifampin, barbiturates) warfarin’s clearance and ↓ the anticoagulant effect.
- Cytochrome P450 inhibitors (amiodarone, SSRIs, cimetidine) ↓ warfarin’s clearance and the anticoagulant effect.
Genetic variability:
- Genetic variability in cytochrome P450 2C9 and VKOR affect responses to warfarin:
- Over/under anticoagulation – dependent on metabolizing status (slow or ultra-rapid)
- Individualized warfarin therapy
Cautions & Adverse effects
- Increased risk of bleeding – chronic hepatic disease or severe renal disease
- Geriatrics: at increased risk of bleeding over 65 yr
- Paediatrics: more susceptible to anticoagulant effects – because of Vitamin K deficiency
Adverse Effects:
- Haemorrhage - due to warfarin toxicity
- Warfarin induced skin necrosis (Breasts, buttocks & thighs)
- Purple-toe syndrome: Rare, painful, purple lesions on the toes and sides of the feet
Direct Oral Anticoagulants (DOACs) vs Warfarin
- DOACs (dabigatran, rivaroxaban) - similar antithrombotic efficacy
- Lower bleeding tendencies - compared to warfarin.
- No need for monitoring
- Fewer drug interactions in comparison to warfarin.
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Description
Explore the critical role of blood clots in the body, including physiological processes involved in hemostasis and the dangers of abnormal clot formation. This quiz covers disorders like von Willebrand disease and hemophilia, as well as thrombus types and their implications for health.
