Thrombosis- Haemostasis in the Wrong Place Flashcards
What is haemostasis?
Haemostasis- coagulation prevents blood loss
Inflammation activates coagulation which promotes inflammation
Coagulation is an inflammatory response
What is thrombosis?
Thrombosis- MRI of brain shows an infarct in left frontal lobe
Ischaemia of the brain caused by embolic stroke wither from the carotids or heart
There is a region of neuronal cell death
Why does coagulation happen?
(First, you have circulating fibrinogen, not activated and doesn’t form strands
Then tissue damage and inflammation causes aggregation and activation of platelets
Thrombin causes fibrinogen conversion to fibrin
The surface of platelets is an important component in the process
The purpose of the entire clotting cascade is to make lots of thrombin so that fibrinogen can be converted to fibrin)
Fibrin forms strands that solidify the agglutinated platelets to prevent blood loss
What is the difference between arterial and venous thrombosis?
Arterial thrombosis:
Mostly result from atheroma rupture or damage to the endothelium (e.g. MI, stroke)
Platelet-rich ‘white’ thrombosis
Mostly primary
May block downstream arteries; by breaking off and going down with the blood flow
Venous thrombosis:
Often results from stasis or a hyper-coagulant state (e.g. DVT)
Platelet-poor ‘red’ thrombus
Mostly secondary
May move to lungs; the next smallest vessels
How does coagulation balance with fibrinolysis?
- Endothelial cells express various factors inhibiting coagulation:
Nitric oxide (inhibit platelets)
Prostaglandin I2 (inhibits platelet activation)
Antithrombin when bound to heparan (inhibits clotting) - Coagulation happens
- If endothelial cells become damaged or inflamed they may favour coagulation, subendothelial cells if disturbed release tissue factor or Von Willebrand factor
Von Willebrand factor (activates platelets)
Tissue Factor (initiates clotting - Clot is broken down by plasmin which is activated from plasminogen by Tissue Plasminogen Activator (tPA)
What is Virchow’s triad?
Stasis- static blood lacks kinetic energy and tends to clot e.g. standing for a long time or being bed-ridden
Hyper-coagulant- e.g. infection/sepsis, genetic predisposition, drugs (e.g. Hormone replacement therapy), pregnancy
Endothelial damage- e.g. surgery or cannula
Any of these out of balance can lead to a blood clot
What is the role of valves in blood control?
Valves in veins prevent backflow of blood
Contraction of nearby muscles squashes veins, acting as a pump to return blood to the heart
If you aren’t moving your legs for while blood tends to pool around
Blood tends to eddy around valves increasing the risk of stasis
What is deep vein thrombosis?
If venous return is blocked, the affected organ becomes congested with fluid
Increased pressure so more filtration
The risk is that the thrombosis might becomes dislodged and make its way back to the heart
What are the possible fates of a thrombus?
Organised- most of it is gone but the endothelium grows over it so vessel a little narrower but normal endothelium
Recanalised and organised- you get holes in the thrombus and insides get covered by endothelium so quite a bit narrower but still normal endothelium
What are two different types of DVT?
Proximal DVT: Higher risk of pulmonary embolism and post-thrombotic syndrome (pain, swelling, maybe even ulcers) due to larger size Distal DVT: In tibial v. or small saphenous v. Rarely cause pulmonary embolism Rarely cause a post-thrombotic syndrome This is because they're small anyway
What is post-thrombotic syndrome?
Inflammation along with damage to the venous valves from the thrombus itself
Valvular incompetence combined with persistent venous obstruction inducing a rupture of small superficial veins, subcutaneous haemorrhage and an increase of tissue permeability
Pain, swelling, discolouration and even ulceration follow
What might be the fate of venous thrombosis in the lungs?
On the left we have a small venous thrombus, as it moves it towards the heart the vessels are getting bigger and bigger where it enters the right atria… and through the pulmonary arteries which get smaller and smaller to the alveoli where they block a small area of the lung leading to necrosis, hypoxia or a little pulmonary oedema.
Sometimes its very minor
This leads to slight VQ mismatch
Now for the worst case scenario where we get a larger thrombus
This one goes into the right atria, into the right ventricle and then it gets lodged in the pulmonary arteries itself causing a saddle embolism, blocking both pulmonary arteries resulting in rapid death
Now usually its something in between these two
How does coagulation happen?
Tissue damage:
Damage to the vessel endothelium exposes underlying subendothelial cells
Von Willebrand factors are expressed by the sub endothelium and binds to platelets
Platelet adherence:
Damaged endothelium exposes Von Willebrand factor on subendothelial cells which activates platelets
Circulating Von Willebrand factor may bind to exposed subendothelial cells
Activated endothelial cells can also express Von Willebrand factor
Platelet activation:
Activated platelets release Thromboxane A2 (TxA2) and Adenosine diphosphate (ADP) which induce receptors for fibrinogen (GPIIb/IIIa)
These bind to receptors on adjacent platelets and increase expression of the glycoprotein complex GPIIb/IIIa
Platelet aggregation:
Fibrinogen acts as a tether, holding platelets together- this is aggregation
Fibrinogen is the soluble precursor to fibrin and is in the circulation
Platelet substrate for coagulation:
Once a clump of platelets aggregate they form a negatively charged surface which is required for coagulation
Coagulation involves:
1. The conversion of fibrinogen to fibrin
2. And then crosslinking of the fibrin clot
What is the purpose of a clotting cascade and the substances in it?
The purpose of the clotting cascades is to produce activated factor ten (Xa) which is a protease that catalyses the conversion of prothrombin (II) to thrombin (IIa)
Thrombin (IIa) is important because it’s a protease that cleaves fibrinogen into fibrin.
Fibrinogen is a large molecule present in plasma- once cleaved it becomes insoluble fibrin
Fibrinogen promotes blood clotting by forming bridges between, and activating, blood platelets through binding to their GpIIb/IIA surface membrane fibrinogen receptor
Fibrin form long polymers which hold activated platelets together in a blood clot.
What is the difference between extrinsic and intrinsic pathways of the clotting cascade?
Extrinsic pathway:
Begins in the vessel wall
Damaged endothelial cells release factor III (tissue factor), the grater the amount of damage, the more is released
Tissue factor combines with calcium on negatively charged platelet surface, and activates factor VII
The VIIa-tissue factor complex can be quickly inactivated by antithrombin III in vivo
Intrinsic pathway:
Begins in the blood stream
Activated when blood exposed to collagen (or other damaged surfaces)
Activated when blood is put onto a charged surface such as glass
Defects in the factors of the extrinsic pathway have far larger physiological effects than mutations in the enzymes of the intrinsic pathway
