Thrombosis Flashcards
What is arterial thrombosis?
A blood clot that develops in an artery
How can atherosclerosis lead to thrombosis?
Rupturing of fibrous cap around a plaque
When a plaque ruptures what stages follow to lead to thrombosis?
Adhesion of platelets to vessel wall
Release of granule contents
Aggregation of platelet to platelet (plug)
Release of co-factors for clotting
Where and how to platelets bind to endothelium?
Platelet GP1a binds Collagen
Platelet GP1b binds Von Willebrand factor (vWf)
What types of platelet granules are there and what do they release?
Platelets contain two types of storage granule a- granules (PDGF, thrombospondin, platelet factor 4, fibrinogen, fibronectin, vWf etc.) and dense bodies (ATP, ADP, GDP, GTP, serotonin, calcium)
How do platelets bind eachother?
Fibrinogen ‘bridges’ stabilise platelet aggregates
Fibrinogen binds platelet surface GPIIb/GPIIIa
What do thrombolytic agents do?
Dissolve existing thrombi
What does streptokinase do?
Enzyme of b-haemolytic Streptococci
Dissolves blood clots by converting plasminogen into plasmin
How is streptokinase given and what is it used for?
Given as iv infusion or via catheter at site of arterial blockage
Used in treatment of acute MI (heart attack) with aspirin
What does recombinant tPA do?
Recombinant human tissue Plasminogen Activator protein
Mode of action accelerated plasminogen cleavage to plasmin
How is recombinant tPA given and what is it used for?
Given as iv infusion or via catheter at site of arterial blockage
Used in treatment of acute MI (with aspirin and heparin)
How does tPA compare with streptokinase?
10x more expensive than streptokinase ($2,200 vs $200)
Clinical trials show slightly increased efficacy compared with Streptokinase
What do antiplatelet agents do?
Interfere with platelet activity
How does aspirin work?
Non-competitive inhibitor of COX-I and COX-2
Acetylates cyclo-oxygenases COX-I and COX-2 (required for TxA2)
Low dose aspirin blocks platelet TXA2 production
What is TXA2?
Thromboxane A2 key mediator of platelet adhesion
What does clopidogrel do?
Blocks activity of platelet ADP
What is abciximab? How does it work?
Abciximab (c7E3) is a chimeric mouse-human monoclonal antibody directed against the platelet GP IIb/IIIa receptor.
Mechanism thought to be steric hindrance of the receptor.
How does warfarin work?
Inhibitor of vitamin K-dependent synthesis of biologically active forms of the clotting factors II, VII, IX and X, as well as the regulatory factors protein C, protein S, and protein Z.
The precursors of these factors require gamma carboxylation of their glutamic acid residues (gamma-glutamyl carboxylase)
This is coupled to the Vitamin K epoxide enzyme (converting reduced vitamin K to vitamin K epoxide)
Warfarin inhibits epoxide reductase (VKORC1) thereby diminishing available reduced vitamin K - which inhibits the carboxylation activity of the glutamyl carboxylase.
What does warfarin inhibit?
Epoxide reductase (VKORC1)
What does warfarin do to vitamin K
Diminishes available reduced vitamin K
What is a venous thrombosis?
Thrombus is a blood clot that forms in situ within a blood vessel that impedes blood flow
What is an embolus?
Embolus is an abnormal mass transported in the bloodstream Venous Thromboembolism (VTE) is where a thrombus forms from blood clotting within a deep vein.
What is thrombophlebitis?
Thrombophlebitis is inflammation of superficial veins due to a blood clot, less serious than deep vein thrombosis (DVT)
What initiates venous thrombosis?
Venous stasis and hypercoagulability - blood clotting in situ
What initiates arterial thrombi?
Platelet activation
What is the most common cause of PE?
DVT
Natural Inhibitors of clot formation
Antithrombin III, thrombomodulin, activated protein C
What is ATIII?
Serine protease inhibitor
What is thrombomodulin?
Endothelial cells produce thrombomodulin which binds to activated thrombin
This complex catalyses the production of activated protein C
What is does activated protein C require for its action?
Vitamin K
How does activated protein C work?
Protein C is activated by thrombin cleavage to become Activated Protein C (APC) that cleaves Activated Factor V and Factor VIII
What is a pulmonary embolism?
DVT travels in the right side of the circulation and becomes trapped in the microvasculature in the pulmonary circulation, reducing perfusion of the lungs.
Risk Factors for Venous Thrombosis
Age
Venous stasis (especially in the elderly)
Any surgery (especially orthopaedic and prostate)
Pregnancy
Infection
Malignancy (especially adenocarcinomas)
Genetic
AT-III deficiency or Protein C Resistance including Factor V Leiden
What is factor V Leiden?
Factor V Leiden raises Relative Risk of VTE massively when combined with other factors
What is Virchow’s triad?
Changes in the intimal surface of the vessel
Changes in the pattern of blood flow
Changes in blood constituents
Why does cancer increase risk of VTE?
Decreased liver production of anti-coagulants
Direct Factor X activation
Autoantibodies to phospholipids
Cancer cells often express Tissue Factor (TF) or induce TF expression in neighbouring stromal cells
Activation of coagulation cascade induces local and systemic inflammation which induces a pro-thrombotic state
What are cardioembolic strokes?
Pooling of blood in the fibrillating left atrium leading to clot formation (turbulence) initially adherent to the atrial wall that may later detach and embolise.
What is another action of herapin?
Heparin stabilises AT III interaction with coagulation enzymes (Factor Xa and Thrombin (IIa))
What are examples of novel oral anticoagulants?
Rivaroxaban
Dabigatran
What is the action of novel oral anticoagulants?
Antagonism of the coagulation cascade Factor Xa (e.g. rivaroxaban) and Thrombin (e.g. dabigatran).
What is factor V leiden?
Mutation in clotting factor that increases risk for blood clots (familial thrombophilia)
What are risk factors for abnormal haemostasis?
Genetic: ATIII deficiency, APC resistance (familial thrombophilia (incl. Factor V Leiden))
Liver damage: can induce ATIII deficiency
Iatrogenic: warfarin/heparin/tPA
Drug used for long term prevention of coronary thrombosis (as distinct from atherosclerosis or
hypertension)
Aspirin
Mode of action: blocks platelet TXA2 production - prevents thromboxane formation
Drug used for existing coronary thrombus?
Streptokinase or tPA
Dissolves blood clots by converting plasminogen into plasmin
Accelerated plasminogen cleavage to plasmin
Vein where DVT commonly occurs?
Femoral vein
In the clotting pathway what is the enzyme that converts fibrinogen to fibrin?
Thrombin (IIa)
Atherosclerosis is a major cause of venous thrombosis?
False
Emboli from arterial thrombi are a major cause of strokes?
True
Plasmin converts fibrinogen to fibrin?
False (its thrombin)
Streptococcus viridans vegetations on heart valves are a source of arterial emboli
True
Carotid arteries are uncommon sites for arterial thrombosis
True
Warfarin is often used to prevent post-operative deep vein thrombosis
True
In the clotting pathway what is the enzyme which that breaks down fibrin?
Plasmin
Histology of the embolus would be most likely to show which one of the following?
Lines of Zahn (clumped platelet strands arranged in ridges - between ridges fibrin, red cells and leukocytes are deposited)
What is the substrate for plasmin?
Fibrin
Venous thrombi are composed mainly of platelets and fibrin
False
Major components of venous thrombi
RBCs and fibrin fibers
Major component of arterial thrombi
Fibrin and platelets
