Clotting part 2/ Atherosclerosis / Lipids Flashcards
What endogenous factor typically supresses coagulation?
Endothelium produces:
Prostacyclin (PGI2)- inhibit platelet aggregation
Nitric Oxide - platelet aggregation inhibition as well as inhibition adhesion of platelets to vascular wall
In plasma, natural anticoagulants (i.e. antithrombin 3 produced by liver)
How does atherosclerosis relate to the clotting cascade?
Plaque rupture releasing contents can initiate coagulation
What is thrombosis?
Occlusion of blood vessel (venous or arterial) by intravascular blood clot or platelet clump
How many platelets are found in blood?
150,000-350,000 per microlitre
What is the role of fibrin?
Helps stabilize the platelet clot to prevent it embolising.
What receptors between platelets and collagen allow for platelet binding and adhesion?
Initial binding - Integrin alpha 2 beta 1 on platelets binds to collagen.
Initial binding allows GP6 receptors on platelet to bind collagen, initiating intracellular signalling
GP1b-9-5 receptor on platelet binds to von Willebrand factors on collagen (this is needed in high shear situations)
What does aspirin target to reduce clotting?
Arachidonic acid pathway, interfering with thromboxane A2 production
What are filopodia and why are they important in relation to coagulation?
They are cytoplasmic projections formed of actin and myosin, found on platelets following activation, which enhance binding and increase area of surface contact
What initiates the intrinsic clotting pathway?
Contact with underlying surface of blood vessel
What is the importance of the platelet production of thrombin?
Thrombin in turn turns soluble fibrinogen into gel-like fibrin which provides strength to blood clot.
It can also activate more platelets
What initiates the extrinsic pathway?
Tissue factor forms complex with factor 7 leading to activation of factor 10
What are some blood clotting disorders?
Von Willebrand Disease (most common)- deficiency of VW factor (it binds and stabilises factor VIII and binds platelets to collagen)
Haemophilia A- Deficiency of factor 8
Haemophilia B- Deficiency of factor 9
Haemophilia C-Deficiency of factor 11 (uncommon, but more common in Ashkenazi Jews), Rosenthal Syndrome
Are any clotting disorders sex specific?
Haemophilia A and B are single X chromosome, therefore only in males
What is tissue plasminogen activator?
Activates plasminogen bound to fibrin into plasmin so it can break down fibrin polymer into soluble degradation products
Can be given to arterial thrombosis stroke victims early in stroke.
What is venous thrombosis?
An intravascular blood clot forms in deep veins, particularly legs.
Fragment may bud off (embolus) and block vessels, commonly pulmonary artery
What is arterial thrombosis?
Platelet aggregate (white), usually at site of ruptured atherosclerotic plaque, then encapsulated by clot (red) Common in coronary arteries (causing MI), or cerebral artery (causing thrombotic stroke) Treatment: dissolve with fibrinolytics, and long term anti-platelet drugs
Where is Von Willebrand Factor found?
Produced by endothelial cells
It is a glycoprotein involved in binding factor 8 when in circulation in order to increase its half life (it dissociates to allow for activation and clotting)
Also binds collagen beneath endothelial surface when damage to vessels occurs, and helps with platelet adhesion via binding (particularly when high shear stress is present)
How do neighbouring platelets bind to eachother?
Fibrinogen and VW Factor acts as a bridge
What is heparin (don’t need to describe its action, just what it is)?
Anticoagulant
Sulphated glycosaminoglycan of variable chain lengths
Polyanionic
Not orally active (need to inject)
What are anticoagulants in vitro?
Heparin
Calcium chelators
Explain the process of platelet aggregation, beginning with platelet adhesion/activation and including role of ADP/TxA2/Thrombin?
Inactivated platelets bind subendothelial domains (i.e. Collagen or VWF) using Integrin alpha-2-beta-1 (also GP6, and GP1b-9-5 to VWF), causing activation of platelet (filopodia extend), and then release alpha and dense granules (ADP).
Released ADP, Thromboxane A2, and activated thrombin bind their respective membrane receptors on platelets, and initiate signalling pathways that convert integrin alpha-2b-beta-3 (aka GP2B3A) from low affinity resting state to high affinity active state (cytoplasmic intramembranous tail opens, conformational change in globular head domain occurs resulting in extended state)
They can now bind extracellular soluble ligands (fibrinogen and VW factor) which act as a bridge, binding to other platelets’ integrin Alpha2b-Beta3 (GP2b-3a) receptors, allowing for aggregation of platelets.
Mechanism of action of heparin?
Binds to and enhances action of endogenous anticoagulant, antithrombin 3
Low doses blocks action of 10a on prothrombin (preventing conversion to active thrombin), whereas large doses will block action of thrombin on fibrinogen.
Immediate
Low MW heparins inhibits factor 10a predominantly
How are unfractionated heparin and low MW heparin different?
Chain of LMWH is shorter
Not long enough to bind both antithrombin and clotting factors, so can inhibit factor 10a, but not the others (as need to bind both anti-thrombin and thrombin together to inhibit this clotting factor 5)
LMWH has high bioavailability, lower incidence of heparin induced-thrombocytopaenia
Don’t need to monitor PTT
Ideal agent during pregnancy
However, it has longer half life and you can’t get full reversal
How are unfractionated heparin and low MW heparin different?
Chain of LMWH is shorter, thus LMWH will inactivate only clotting factor X (10), whereas unfractionated will inactivate both factor 10 and thrombin (and will do so much quicker than LMWH).
LMWH has high bioavailability, lower incidence of heparin induced-thrombocytopaenia
Don’t need to monitor PTT
Ideal agent during pregnancy
However, it has longer half life and you can’t get full reversal
What are side effects of heparin?
Allergic reactions
Haemorrhage
Heparin induced thrombocytopaenia
What is warfarin and how does it work?
Structural analogue of vitamin K
blocks synthesis of coagulation factors (2,7,9,10) in liver via antagonizing vit k
This means delayed onset of action
What is warfarin and how does it work?
Structural analogue of vitamin K
Blocks carboxylation of coagulation factors (2,7,9,10) in liver via antagonizing vit k (warfarin inhibits vitamin k reductase which is needed to reduce (activate) vitamin K- no reduction results in no conversion from inactive to active clotting factors by gamma-glutamyl carboxylase).
This means delayed onset of action
When is warfarin used?
Venous thrombosis
Preventing pulmonary embolism, embolism in patients with atrial fibrillation
Prophylaxis of thrombosis after insertion of prosthetic heart valves
When is warfarin used?
Venous thrombosis
Preventing pulmonary embolism, embolism in patients with atrial fibrillation
Prophylaxis of thrombosis after insertion of prosthetic heart valves
What are important characteristics in regards to warfarin?
Orally active, but delayed onset
99% bound to plasma albumin (but it can be displaced by aspirin (and other NSAIDs) which can increase haemorrhage risk)
Can cross placenta
What are some newly introduced oral anticoagulants?
Dabigatran Exilate- direct thrombin 2a inhibitor Rivaroxaban- direct factor 10a inhibitor Active immediately Shorter half -life No antidotes
What activates platelets?
Collagen exposure
Thrombin
Thromboxane A2, ADP, and 5-Hydroxytryptomine synthesized by adjacent platelets
What are ways in which the vessel wall prevents platelet aggregation?
Endothelial cells release:
NO raises cGMP in platelets
PGI2 raises cAMP in platelets
both have anti-platelet activity
How does aspirin work as an anti-thrombotic agent?
Irreversibly inhibits cyclooxygenase via acetylation of terminal serine
How does dipyridamole work to inhibit platelet activation?
Inhibits cyclic nucleotide phosphodiesterases which results in increase cAMP and cGMP
Essentially works as copy cat for NO and prostacyclin
How does epoprostenol work?
Its a stabilized prostacyclin with a short half life
Used during haemodialysis to inhibit platelet activation
Given intravenously
How does Clopidogrel work?
Blocks platelet ADP receptors, preventing GP2b-3a receptors exposure (which is needed for linking platelets to each other)
Used to prevent re-infarction (by 20%)
Used in combo with aspirin
How does Abciximab work?
Blocks GP2b-3a receptors exposed by any pathway (preventing platelets from adhering to each other)
Used during surgical exploration
What does tissue plasminogen activator do?
Produced by vascular endothelium
Activates plasminogen bound to fibrin, meaning its selective to clots
What is streptokinase?
Non-selective thrombolytic enzyme
Used in STEMIs
Activates plasminogen systemically, causing conformational changes
What are examples of scenarios which may require the use of fibrinolytics?
Treatment of a ST segment elevation myocardial infarction (STEMI),
Acute stroke
Pulmonary embolism
Acute deep venous thrombosis
Why are anti-coagulants used to prevent venous thrombosis and antiplatelets arterial thrombosis?
Because arterial circulation is fast moving, and thrombi are rich in platelets, therefore anti-platelets are used.
Venous circulation is much slower and thrombi is largely composed of fibrin, hence the use of anticoagulants
