Haemostasis Flashcards
What is haemostasis?
The mechanism for stopping bleeding from damaged blood vessels.
What is thrombosis?
The formation of a blood clot inside a blood vessel.
How does haemostasis occur?
Components of the blood work together to drive haemostasis and the formation of blood clots - thrombi - which work to prevent blood loss after injury.
The clots are then cleared and the vessel repaired.
This involves, white blood cells, platelets and proteins.
What is chronic thrombosis?
Pathological thrombus formation can cause chronic thrombosis, which can occlude blood vessels and cause downstream tissue ischaemia.
This can cause heart attacks, strokes and deep vein thrombosis.
Continued thrombus formation can be caused in atherosclerosis if the plaque ruptures it causes lots of platelet activation.
What are the stages of haemostasis?
- Vasoconstriction - driven by the vessel wall.
- Activation of platelets and formation of the primary haemostatic plug.
- Coagulation, fibrin formation and clot retraction, forms the secondary haemostatic plug, using thrombin and plasma.
- Fibrinolysis by plasmin.
What is vasoconstriction?
A reflex response to injury that causes local constriction of blood vessels.
How is vasoconstriction triggered?
Direct injury to vascular smooth muscle cells.
Molecules released from injured endothelial cells.
Molecules released from activated platelets.
Neuronal signals from local pain receptors.
What is the effect of vasoconstriction?
Reduces blood flow to injured areas, so reduces blood loss.
Increases the likelihood of contact activation of platelets and coagulation factors, by producing turbulent and slower flow.
Reduces chance of further clots forming.
What are platelets?
Resting platelets are small, biconvex discs.
They have a life span of 8 days - rapid turnover and clearance.
This is because the ability to respond of the platelet reduces with age, so they are quickly turned over.
Platelets have no nucleus - so cannot generate new proteins.
How are platelets activated?
Platelets travel through the bloodstream in resting form.
When they meet damaged vessels, there is rapid interaction with surface receptors which drive activation.
Signals can either be soluble or vessel wall signals.
What are vessel wall activatory signals?
When there is damage there is a change in the wall - either endothelium is removed, or activated, or the underlying muscle cells are exposed.
So this exposes the platelet receptors to factors it is not normally in contact with - like collagen and VWF.
Glycoprotein receptors GPVI, asB1 integrin and GPIb-IX-V recognise these and activate the platelet and then cause adhesion.
What are soluble activatory signals?
Soluble factors like thromboxane, thrombin and ADP bind to receptors and activate the platelets.
These are GPCRs such as TxA2, PAR1 and P2Y12.
What do the platelets do when activated?
Platelets change shape, from biconvex disc to spiky round cells that spread out and adhere to cells.
Secrete granules - upon activation granules are brought to the surface and allows contents to do work.
Become sticky and aggregate - stick together, form clots at blood vessel wall.
What is the shape change in platelets?
Platelets become a distinctive shape
This is driven by cytoskeleton rearrangements - tubulin ring changes, actin forms adhesions, and their coordinated response allows adhesion.
Platelets can change shape to have a bigger surface area for interaction with other platelets to form the plug.
What is the importance of shape change in platelets?
Plugs the damage to the vessel.
Makes platelets more likely to stick together.
What do platelets secrete?
Two main types of granules
a granules
Dense granules - smaller and less, have electron dense core.
Upon activation granules are brought to surface, membrane fuses and releases content to environment.
Other granules such as lysosomes secrete hydrolases.
What are a-granules?
Contain cell mitogens, haemostatic factors, adhesion proteins, platelet receptors, and leukocyte recruitment factors.
This leukocyte recruitment helps stop infection occurring at the site of damage.
The proteins promote repair - growth factors stimulate fibroblasts.
Adhesion proteins help the platelets stick together.
What are dense granules?
Contain platelet agonists e.g. ADP and ATP, metal ions, and haemostatic cofactors.
They are mainly for activation and coagulations.
What is the importance of platelet granule secretion?
Reinforces platelet activation.
Activation of coagulation cascade
Drives vessel wall and tissue repair.
How do the platelets become sticky?
The signalling particles target the a2B1 integrin, which is highly expressed and important for sticking.
Integrin is present in the blood in the inactive form.
When activated, it binds fibrinogen, causes cross-bridges to form, so the clot builds up and platelets aggregate together.
What does an undamaged endothelium look like?
There are nitric oxide and prostacyclin being produced so there is a constant low level of vasodilation.
The blood and platelets flow through easily.
What is the formation of the primary haemostatic plug?
The endothelium is damaged, the nitric oxide signals disappear.
The collagens and matrix proteins are exposed.
VWF binds to collagen and provides a highly reactive surface to platelets, which roll along it and stick, forming a plug and spreading out.
Other platelets can then bind, and the granules release soluble signals into the local environment to activate the new platelets.
What is the formation of the secondary haemostatic plug?
Fibrinogen is a soluble protein bound to the platelets, linking them together.
Thrombin is generated, which is a protease that converts fibrinogen to fibrin, which is insoluble, so can be cross-linked and forms secondary aggregate at the site of injury.
So thrombin generation drives formation of the insoluble mesh around the aggregate to make it a stable blood clot.
What is the coagulation cascade?
The process by which thrombin is generated from the precursor prothrombin.
It involves step wise activation - each step provides an amplification of the signal - so there is lots of thrombin and it can act quickly.
The cascade also has negative feedback loops to ensure local and limited thrombin generation.
What is fibrinolysis?
Fibrinolysis is the breakdown of the fibrin clot.
During blood vessel damage, factors are released that bind to fibrin and recruit plasminogen to the clot.
Plasminogen is converted by a fibrin bound protease to plasmin.
Plasmin then degrades fibrin.
The proteases are bound to fibrin so act locally at the site of the clot.
What does localisation of fibrinolysis to fibrin in the clot help with?
Limits fibrinolysis to the site of injury.
Helps prevent excessive thrombus growth.
