Week 2: The Coagulation System Flashcards
What is Haemostasis?
The normal response of the vessel to injury of liming bleeding by forming a clot at the site of injury while maintaining blood flow to rest of vessel
Removal of the blood clot following wound healing
What is thrombosis?
The pathological manifestation of haemostasis
Causes restriction or blockage of blood vessel, causing hypoxia or tissue damage
Thrombi can also dislodge, leading to embolization
What are the three stages of haemostasis?
1) Vascular Spasm - Damaged blood vessels constrict and reduce blood flow to that area
2) Platelet Plug Formation - (Primary Haemostasis) Platelets bind to the damaged vessel wall and form a platelet plug.
3) Coagulation - ( Secondary Haemostasis) A stable clot forms by converting fibrinogen to fibrin
What are platelets fragments of?
Megakaryocyte cytoplasm
What is the physiological range of platelets in blood?
150-400 x 10^9/L of blood
What is the lifespan of platelets?
5-9 days
What are old platelets destroyed by?
Kupffer cells in the liver or phagocytosis by spleen
Platelet Ultrastructure (Anatomy)
What are the critical components of platelets?
Membrane proteins
Secretory Granules
Surface-Connected open cannalicular system (SCOCS)
What do alpha granules contain?
1) Adhesive proteins (fibrinogen, fibronectin, vWF)
2) Platelet specific Protein (PF4, PDGF)
3) Membrane Proteins (GPIIBIIIA and other glycoproteins for adhesion processes)
4) alpha granules specific proteins (p-selectin)
What do dense granules contain?
Vasoconstrictive agents (serotonin) Platelet Agonist (ADP, ATP) - activate other platelets Calcium and Magnesium - to activate integrins on the platelet surface
What is the GPIIb-IIIa complex?
vWF interaction, fibrinogen binding and platelet aggregation
How does platelet adhesion happen?
1) When the blood vessel is damaged, the sub endothelial layer is exposed which has collagen and immobilised vWF factor.
2) The platelets adhere to collagen proteins and are tethered to the subendothelium and sheer stress is a critical component of tethering.
3) Blood flow then rolls the platelet along the subendothelium promoting more GPIB/vWF association and creates firmer adhesion.
4) This firmer adhesion allows the initiation of platelet activation resulting in granule release and conformation changes in specific adhesion molecules leading to stronger adhesion, shape change and further activation
How does a platelet plug form?
The activated platelet monolayer release platelet agonists from their granules such as ADP, thromboxane A2 and adhesive proteins, such as fibrinogen, which recruits further platelets to the developing plug.
As new platelet are recruited, they change shape and form pseudopodia allowing for greater platelet-platelet interactions, especially via fibrinogen cross bridges which bind to GPIIbIIIa.
What are coagulation factors?
a group of zymogens which cooperate in an integrated system of enzyme activation and inactivation steps
The coagulation cascade is initiated along which 2 pathways?
Extrinsic (trauma)
Intrinsic (Blood vessel damage)
What is the product of the coagulation cascade?
A gelatinous but robust clot made up of a mesh of fibrin, an insoluble filamentous protein derived from fibrinogen in which platelets and blood cells are trapped.
What are the stages of the coagulation cascade?
What are the stages of the coagulation cascade?
What are anticoagulants in the coagulation cascade?
Tissue factor pathway inhibitor expressed and released by endothelial cells that line blood vessels and other tissues
Anti Thrombin is constantly found in the circulation
What initiates the extrinsic pathway for the coagulation cascade?
Factor 3 - Tissue Factor which all cells have and when cells are damaged or crushed, tissue factor is released.
What does Tissue Factor Pathway inhibitors act on?
What does Anti-thrombin act on?
What is the purpose of anti-coagulants?
To prevent unnecessary coagulation
What is the purpose of anti-coagulants?
To prevent unnecessary coagulation
What is platelet aggregometry?
It is the measure of light passing through a plasm rich platelet fluid depending on whether the platelets are inactivated(cloudy) or activated(more aggregated so light can pass through)
What can reduce platelet aggregation in tests?
Certain agonists can reduce aggregation
What is the coagulation test?
Time taken for the ball in the plasma to stop flying due to coagulated plasma.
Prothrombin time - Extrinsic Pathway
Partial Thromboplastin time - Intrinsic Pathway
What information can a PT or PTT give you?
What is Thrombocytopenia?
A condition of low amounts of circulating platelets. Primary thrombocytopenia is when there are low platelets counts occur spontaneously for an unknown reason
What is immune thrombocytopenia?
60% of primary thrombocytopenia cases are this where antibodies to platelets are found in the plasma. The IgG-coated platlets are then cleared either by splenic macrophages or kupffer cells in liver. This can cause extreme ITP.
What is Glanzmann’s Thrombastenia?
It is a autosomal recessive bleeding syndrome affecting the megakaryocyte lineage and characterized by the lack of platelet aggregation.
Specific mutations lead to changes in the expression and/or function of GPIIb and/or IIIa. This severely affects function and platelet aggregation.
What is Haemophillia?
A recessive sex-linked X chromosome disorder and characterized by changes in clotting proteins.
Haemophillia A is the deficiency of FVIII
Haemophillia B is a deficiency of FIX
What is thromboxane A2?
It is released by platlets and is a potent vasoconstrictor and stimulus for platelet aggregation
What is the mechanism for aspirin?
Inhibits platelet cyclooxygenase, a key enzyme in thromboxane A2 generation.
Thromboxane A2 triggers reactions that lead to platelet activation and aggregation.
Aspirin acts as a potent antiplatelet agent by inhibiting generation of this mediator
These effects last for the life of the platelets, approximately 7-10 days
What 2 effects of aspirin go hand in hand?
Anti thrombotic as it inhibits COX 1 and therefore inhibits thromboxane
Anti inflammatory as it acetylates COX2 to form lipoxin
What are adverse side effects of Aspirin?
GI Bleeding
Hemorrhagic Stroke
Aspirin Doses
Low Dose - 81mg/day this dose can maximally inhibit platelet activity and can be taken daily
High Dose - 325mg/day this is used for initial treatment of acute symptom like MI
How does Clopidogrel work?
Clopidogrel is an ADP inhibitor and binds to the receptor P2Y12 which is the most potent driver or platelet aggregation but leaves receptors P2Y1 AND P2X1 alone so can get a low level of platelet activation
What is the clinical use for ADP receptor antagonists?
prevent blockage of coronary artery stents
reduce thrombotic events
Why is clopidogrel a pro drug?
It gets metabolized into its active form by the liver b hepatic cyp2c19 (enyme).
What are the adverse side effects of ADP receptor antagonists?
bleeding
thrombotic thrombocytopenic purpura
What are the adverse side effects of ADP receptor antagonists?
bleeding
thrombotic thrombocytopenic purpura
What are the primary mechanisms of action for anti-coagulants?
Inhibit the synthesis of clotting factors
Inhibit the activity of clotting factors
What is the primary goal of anticoagulants?
To reduce the formation of fibrin
What are the types of inhibitors that anticoagulants can be grouped into?
1) Direct Thrombin Inhibitors
2) Direct Factor Xa inhibitors
What is heparin?
Heparin is a hetrogenous natural polysaccharide which is an anti coagulant and there are fractionated and unfractionated types of heparin that works with Anti thrombin to target Factor 10 and thrombin.
How does Heparin work?
Unfractionated Heparin (UFH) binds to AT causing a conformational change which increases its binding affinity for FXa and thrombin. The inactivation of thrombin is achieved by UFH and AT complex forming a ternary structure with thrombin and permanently inhibiting thrombin. It also factor 10 but not permanently.
What does low molecular weight heparin do?
LMWH can only inactivate FXa and cannot form a ternary structure with thrombin
What are the clinical indications for heparin use?
What is Warfarin and its mechanism?
Vitamin K antagonist
Many clotting factors rely on the reduced form of vitamin K (KH2) for carboxylation of glutamic residues
Warfarin blocks the reformation of KH2 from the oxidised form (KO), thereby reducing the formation of clotting factors
Adverse side effects of heparin
Bleeding
Immune induced thrombocytopenia as heparin coats thrombin/FXa
Neurological injury with epidural
Risk increased when drug is used in conjunction with anti-platelet and anti-thrombotic drugs.
Adverse Side effects of Warfarin
Bleeding
Foetal Hemorrhage
long term use can cause osteoporosis
