L13 - Blood formation and clotting Flashcards
Where is there a high / low blood pressure in terms of blood vessels?
High blood pressure - arteries
Low blood pressure - veins
What happens when blood vessels become damaged?
Blood can leak out into surrounding tissues
- (haematoma (vs bruise))
What is the bodies immediate response to a damages vessel?
To constrict
- opposing endothelial surfaces can temporarily glue together
What can blood clotting dysfunction lead to?
Bleeding disorders
What 2 phases can blood clotting be broken down into?
- primary haemostasis: platelet plug formation
- secondary haemostasis: blood clotting mech to transform and stabilise weak platelet plug into clot by fibrin network
What can damage to endothelial cells expose?
The subendothelial layers consisting of connective collages fibres
How do platelets adhere to these collagen fibres via?
Intermediate protein called von Willebrand factor (vWF)
What does platelet binding cause?
Release of ADP and serotonin from their secretory vesicles
= platelet activation
What does platelet activation cause?
causes change in shape and surface protein expression
What is platelet aggregation?
When platelets adhere to each other to form a plug
What enhances activation and aggregation?
Synthesis and release of thromboxane A2
What is the plug stabilised by?
Fibrinogen bridges
- receptors on platelet surface become exposed during activation
What causes contraction of plug? (2)
Actin and myosin
- binding it tightly together
Smooth muscle in vessels
- mediated by TxA2 + other chems from platelet granules
What do healthy endothelial cells synthesise? (For restriction of platelet plug spreading) (2)
- prostacyclin (prostaglandin I2, PGI2)
- Nitric oxide (vasodilator)
Both potent inhibitors of platelet activation
What is a clot?
(Thrombus)
The transformation of blood into a gel consisting of fibrin polymers
- occurs arounf the platelet plug
What do damaged vessels activate?
Cascade of enzymes that result in the activation of an enzyme called thrombin
What does thrombin cleave?
Protein called fibrinogen into fibrin molcules that bind together to form a loose meshwork
What are the steps that take place after a blood vessel is damaged? (3)
- damaged blood vessel
- formation of platelet plug
- development of clot
What happens at each step of blood clotting?
Inactive plasma protein is cleaved to become an active enzyme or cofactor activating the next step of the pathway
What is a key step in blood clotting?
Activation of prothrombin to thrombin which then cleaves and activated fibrinogen to fibrin
What happens once thrombin activates?
Has a positive feedback on other factors which lead to more thrombin activation
Where is the extrinsic pathway of the clotting cascade initiated
by tissue factor located on the outer leaflet of the plasma membrane of cells found in sub endothelial tissue
What does the extrinsic pathway activate?
FVII and FX
What is the normal way to activate clotting in the body?
Extrinsic pathway via tissue
- generates small amounts of thrombin
- feeds back to intrinsic pathway to activate components and generate more
Where is everything required to activate intrinsic cascade found?
In the blood
What does intrinsic pathway start with? And what does it acts as?
Activation of FXII by contact with collagen
- essential cofactor
What is intrinsic pathway triggered like in vivo?
Sequentially after extrinsic pathway
What is the role of the liver?
The site of many clotting factors
- produces bile salts require for absorption of vit K for the production of prothrombin
What do patients with liver disease often have?
Bleeding problems
What is thrombin?
Enzyme
- recruits the intrinsic pathway, enhances prothrombin conversion to thrombin by activating factor V and platelets
What do platelets express?
A receptor called the Protease activated receptor (PAR)
What are the 4 anti-clotting mechanisms?
- PGI2, NO, endogenous anti-coagulants (inhibition of platelet activation)
- Endothelial cell production of tissue factor inhibitor
- Thrombin binds to endothelial cell receptor thrombomodulin (activates protein C = inactivates FV and VII)
- Plasma protein antithrombin II (inactivate thrombin, other clotting factors
How is the clot dissolved?
Fibrinolytics
- tissue plasminogen activator (t-PA) released by EC
- binds to fibirin clot and is stabilised to activate plasmin
Examples of clotting disorders and treatments
Damage to endothelium: myocardial infacrtion, atherosclerosis
Clots: deep vein thrombosis, pulmonary embolism
Clotting disorders: haemophilia
Aspirin, heparin, warfarin, recombinant t-PA
