3. Thrombosis Flashcards
What is thrombosis?
Pathological formation of an intravascular blood clot
Where may thrombosis occur?
In veins or arteries
What are lines of Zahn?
-Lines of Zahn are alternating layers of platelets, fibrin, and red blood cells found in thrombi (blood clots) that form inside flowing blood vessels.
-They help distinguish pre-mortem thrombi (formed before death) from post-mortem clots (which lack these layers and settle uniformly).
What are the components of Virchow’s Triad?
-Endothelial injury (Damage to the blood vessel lining (endothelium))
-Hypercoagulability (Increased tendency of blood to clot)
-Stasis (disruption of blood flow)
What is the action of NO on platelets?
-Inhibits platelet aggregation: NO prevents platelets from sticking together, reducing clot formation.
-Prevents platelet adhesion to vessel walls: This helps maintain normal blood flow and prevents thrombosis.
-Reduces platelet activation: By increasing cGMP levels, NO reduces platelet sensitivity to clotting signals.
Give some causes of disruption of blood flow/stasis leading to thrombosis
-Immobility (long flights, bed rest)
-Varicose veins
-Cardiac wall dysfunction (post MI)
-Aneurysm
-Atrial fibrillation
Give some causes of endothelial damage leading to thrombosis
-Mechanical damage eg atherosclerosis
-Inflammatory damage eg vasculitis
-Chemical damage eg tobacco smoke
Give some causes of hypercoagulable states leading to thrombosis
-Genetic causes eg Anti-Thrombin 3 deficiency
-Acquired causes eg diffuse intravascular coagulation
-Pharmacological factors eg oestrogen based oral contraceptives
What are the types of thrombi?
-Venous
-Arterial
-Post mortem
Describe the characteristics of arterial thrombi
-Location: Form in high-pressure arteries.
-Composition: Rich in platelets and fibrin (white thrombi).
-Appearance: Pale, firm, and adherent to vessel walls.
-Cause: Often due to endothelial injury (e.g., atherosclerosis, hypertension).
What are used to prevent arterial thrombi?
Inhibitors of platelet aggregation, eg aspirin
Describe the characteristics of venous thrombi
-Location: Found in low-pressure veins (e.g., deep leg veins).
-Composition: RBC-rich with fibrin (red thrombi).
-Appearance: Dark red, loosely attached, may have a “tail” extending with blood flow.
-Cause: Often due to stasis or hypercoagulability (e.g., immobility, cancer, pregnancy).
What are used to prevent venous thrombi?
-Warfarin and other anticoagulants
-Do not dissolve clot but prevent further formation via the fibrinolytic system
What are the stages of platelet formation?
-Adhesion
-Platelet activation
-Aggregation
Describe what occurs in the platelet activation stage of clot formation
Platelets undergo shape change and degranulation, whereby compounds are released
What is released in degranulation of platelets
-ADP: Activates more platelets.
-Thromboxane A2 (TXA2): Promotes vasoconstriction & platelet aggregation.
-Serotonin: Enhances vasoconstriction.
Describe the action of thrombin
-Conversion of Fibrinogen to Fibrin monomers, which then polymerise
-activates Factor XIII, which cross-links fibrin fibers, stabilising the fibrin polymer into a firm mesh
-Acts in a feedback loop to activate several other coagulation factors (V, VIII, XI) and is therefore pivotal in the amplification system
Describe the action of plasmin
-Breaks down clot
-Cleaves fibrin and fibrinogen into fibrinogen degradation products (FDPs)
-Form fragments known as D dimers
-Degrades some clotting factors
-Blocks platelet aggregation
What is prothrombin time (PT)?
Prothrombin Time (PT) is a laboratory test that measures how long it takes for blood to clot via the extrinsic and common coagulation pathways. It is used to assess clotting function and monitor anticoagulant therapy (e.g., warfarin)
Describe how prothrombin time (PT) works
-The test involves adding tissue factor (thromboplastin) and calcium to a blood sample.
-The time taken for a fibrin clot to form is measured in seconds.
-PT is often reported as International Normalized -Ratio (INR) to standardize results.
What is the normal reference Prothombin time (PT) range?
Normal reference range is 11-15 seconds, however this varies in different laboratories
What is the international normalised ratio of PT
-The International Normalised Ratio (INR) is a standardised way to measure how long blood takes to clot, based on the Prothrombin Time (PT) test, ensuring consistency across different labs.
-Normal INR: 0.8 – 1.2
What does a high versus a low PT INR indicate?
-Higher INR (>4) → Increased bleeding risk.
-Lower INR (<2) → Risk of clot formation.
Give the classes of drugs developed to prevent or reverse thrombus formation
-Anticoagulants
-Antiplatelet agents
-Fibrinolytic agents
Describe the mechanism of action of anticoagulants
-Anticoagulants are drugs that reduce blood clot formation, preventing conditions like deep vein thrombosis (DVT), pulmonary embolism (PE), and stroke.
-They work by targeting different parts of the coagulation cascade
Give examples of types of anticoagulants, and examples
-Vitamin K antagonists (eg warfarin)
-Direct factor Xa inhibitors (eg rivaroxaban)
-Direct thrombin inhibitors (eg Dabigatran)
-Heparins (eg low molecular weight heparin)
Describe the mechanism of action of anti-platelets
Antiplatelet drugs reduce platelet aggregation, preventing the formation of arterial thrombi, which are common in heart attacks, strokes, and atherosclerosis-related conditions.
Give examples of types of antiplatelets, and examples
-Cyclooxygenase inhibitors (eg aspirin)
-ADP/P2Y12 receptor antagonists (eg clopidogrel)
-PDE inhibitors (eg Dipyridamole)
Give examples of types of fibrinolytics, and give examples
-Tissue Plasminogen activators (eg Alteplase)
-Non specific Plasminogen activators (eg Urokinase)
Describe the mechanism of action of fibrinolytic agents
-Fibrinolytic agents (also called thrombolytics) break down blood clots by activating plasminogen to form plasmin, which degrades fibrin.
-These drugs are used in acute ischemic stroke, myocardial infarction (STEMI), and pulmonary embolism (PE) to restore blood flow.
Describe the steps taken in the case of venous thromboembolism
-Direct acting oral anticoagulants (Apixaban or reivaroxaban) on confirmed proximal DVT or Pulmonary Embolism
-If apixaban or rivaroxaban are contraindicated: use low molecular weight heparin (followed by dabigatran etexilate or deoxaban) OR LMWH given with a vitamin K antagonist for at least 5 days or target INR achieved followed by a vitamin K antagonist on its own.
-Patients undergoing surgery where there is a risk of thrombosis are given thromboprophylaxis
Describe the mechanism of action of Direct acting oral anticoagulants, Dabigatran etexilate
-Reversible inhibitor of thrombin
-Idarucizumab reversal agent
Describe the mechanism of action of Direct acting oral anticoagulants
-Reversible inhibitors of activated factor X (factor Xa) Andexanet alfa reversal agent
-Prevents thrombin generation
-Prevents thrombus development
What are Direct Acting Oral Coagulants (eg Apixaban, Dabigatran etexilate, edoxaban, rivaroxaban) used for?
-Prevention of stroke
-Secondary prevention of DVT and/or PE
-Prevention of venous thromboembolism following surgery (except edoxaban)
What is rivaroxaban used for?
-Prevention of atherothrombotic events in patients with coronary or peripheral artery disease
-following an acute myocardial infarction
Give the contraindications associated with apixaban
-Avoid in conditions with significant risk of bleeding
-Gastrointestinal ulceration
-Malignant neoplasms with high risk of bleeding
-Oesophageal varices
-Elderly: prescription potentially inappropriate (STOPP criteria) with risk of bleeding eg with severe hypertension
-Side effects: anaemia and haemorrhage
Describe Heparin
-Family of sulphated mucopolysaccharides found in the secretory granules of mast cells
-Commercial preparations vary in MW from 3,000 to 30,000Da
-Inhibits coagulation by activating antithrombin III
-AT3 is a naturally occurring inhibitor of thrombin and clotting factors IX, Xa, XI and XII
-In the presence of heparin, AT3 becomes 1000x more active and inhibition of clotting factors is instantaneous
Describe LMWHs (low molecular weight heparins)
-Fragments or synthetic heparin, have more consistent activity
-Inactivate Xa (and thrombin) also via activation fo AT3
-Heparin and LMWH have immediate onset of action
Describe the pharmacokinetics of Heparin and LMWHs
-Inactive when given orally
-Administered IV or SC (SC for LMWHs)
-Heparin has a short half life, must be given frequently or as a continuous infusion
-LMWH have longer duration of action, allowing for once a day dosing
-Eliminated mainly by renal excretion, care needed for patients with renal disease
-Side effects include bleeding and hypersensitivity
-Overdose treated by IV protamine (strongly basic protein)
Describe Vitamin K antagonists
-Inhibits the activation for vitamin K1 dependent clotting factors II, VII, IX and X
-At least 48 to 72 hours for the anticoagulant effect to develop
-A small population of patients is genetically resistant to warfarin, due to reduced binding to vitamin K reductases
-Side effects include haemorrhage and skin necrosis
Describe how warfarin inhibits clotting
-Clotting factors require reduced vitamin K to be activated.
-Warfarin inhibits Vitamin K reductase.
Describe the pharmacokinetics of warfarin
-Absorption: rapidly and almost totally absorbed form the GI, levels peak in blood ~0.5-4 hours after administration
-Distribution: low volume of distribution as ~99% plasma protein bound (mainly to albumin)
-Metabolism: Action is terminated by metabolism in the liver by CYP2C9, CYP2C19 and CYP3A4
-Excretion: metabolites are conjugated to glucuronide and excreted in urine and faeces
-Half life of 15-80 hours, meaning dose is very variable
Describe how anti platelets are used as prophylactics
-Platelets provide the initial haemostatic plug at sites of vascular injury.
-Inhibition of platelet function is a useful prophylactic and therapeutic strategy against MI and stroke caused by thrombosis
Describe the mechanism of action of aspirin
-Irreversibly inhibits COX1, therefore inhibits the synthesis of TXA2
-Because platelets do not contain DNA or RNA they cannot synthesise new COX1
-Inhibition is irreversible and effective for the life of the circulating platelet (7-10 days)
Describe the clinical use of aspirin
Clinical use: Used prophylactically to prevent arterial thrombosis leading to transient ischaemic attack, stroke and MI
When and how are fibrinolytics administered?
-Administered IV for immediate effect
-Short half life
-Main hazard is bleeding
-Used nowadays for restoring catheter and shunt function, lysing clots causing occulisons, Dissolving clots resulting in strokes
What do high blood pressure and anticoagulants increase the risk of?
Bleeds
If thrombolytics are given during hemorrhagic stroke or gastric ulcer, what may occur?
The clot will not form to stop the bleed
